Abstract Tissue regeneration therapy is a major endeavour in modern biology. Its success is dependent upon our ability to control cell fate decisions in adult tissue stem cells (SCs). Intrinsic genome plasticity and the crosstalk between SCs and their environment are important factors in cell fate decisions. Specialized epigenetic states, and particularly the genomic distribution and overall levels of covalent histone modifications (e.g. acetylation, methylation), are important for SC fates and for disease. Many small molecule inhibitors have been developed over the past decade to perturb histone modification levels, and some have already been implemented as cancer drugs in clinical trials. However, little has been done to manipulate levels of histone methylation in adult tissue SCs for possible control of tissue regeneration. Recently, we reported a global hypomethylation of histone H3 K4/9/27me3 that occurs at catagen in mouse skin, including in the quiescent hair follicle stem cells (HFSCs). Based on our preliminary data we hypothesize that perturbation of H3 K4/9/27me3 levels allows manipulation of tissue regeneration by engaging with signalling pathways essential in quiescent SCs. Here we use a combination of small molecule targeting and our newly developed mouse genetic tools to manipulate the levels of H3 K4/9/27me3 in adult mouse skin, and examine effects on tissue regeneration (e.g. hair follicle cycle and wound healing). We also begin to examine molecular mechanisms upstream and downstream of H3 K4/9/27me3 levels in HFSCs. In particular, we address for the first time in an adult mouse tissue in vivo the difference between steady state mRNA levels and nascent RNA levels and establish the direct link with histone methylation levels. Our work has implications for understanding the basic science of genome plasticity in quiescent tissue SCs and for examining the use of epigenetics-targeting drugs to skin and hair follicle regenerative therapies.